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  • Munck-Wikland, Eva  (8)
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  • 1
    Language: English
    In: International Journal of Cancer, 01 January 2013, Vol.132(1), pp.72-81
    Description: Human papillomavirus (HPV) is an important factor for the development of tonsillar squamous cell carcinoma (TSCC). In addition, patients with HPV‐positive TSCC have a better clinical outcome than patients with HPV‐negative TSCC. Although, HPV is an important prognostic marker, additional biomarkers are needed to better predict clinical outcome to individualize treatment. Hence, we examined if classical HLA HLA‐A,B,C and nonclassical HLA‐E,G could serve as such marker. Formalin‐fixed paraffin‐embedded TSCC from 150 patients diagnosed 2000–2006, earlier analyzed for HPV DNA and p16, and treated with intention to cure were evaluated for the expression of HLA‐A,B,C and HLA‐E,G by immunohistochemistry. For HPV‐positive TSCC a low expression of HLA‐A,B,C, whereas for HPV‐negative TSCC, a normal expression of HLA‐A,B,C was significantly correlated to a favorable clinical outcome. These correlations were more pronounced for membrane staining of HLA‐A,B,C when compared with cytoplasmatic staining. No significant correlation was found between HLA‐E,G and HPV status or clinical outcome. The unexpected contrasting correlation between HLA‐A,B,C expression, and clinical outcome depending on HPV, indicates essential differences between HPV‐positive and HPV‐negative TSCC. Furthermore, our data demonstrate that for both HPV‐positive and HPV‐negative TSCC, the expression of HLA‐A,B,C together with HPV may serve as a useful biomarker for predicting clinical outcome.
    Keywords: Human Papillomavirus ; Oropharyngeal Squamous Cell Carcinoma ; Tonsillar Squamous Cell Carcinoma ; Prognosis ; Head And Neck Cancer ; Hla Class I ; Treatment
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 2
    Language: English
    In: European Journal of Cancer, August 2015, Vol.51(12), pp.1580-1587
    Description: To combine clinical and molecular markers into an algorithm for predicting outcome for individual patients with human papillomavirus (HPV) DNA/p16 positive tonsillar and base of tongue squamous cell carcinoma (TSCC and BOTSCC). Head-neck cancer treatment has become more intensified, comprising not only surgery and radiotherapy, but also induction/concomitant chemotherapy and targeted therapy. With less treatment, 3-year disease free survival (DFS) is 80% for HPV-positive TSCC and BOTSCC. An 85–100% 3-year DFS is observed for HPV TSCC and BOTSCC with absence of HLA class I, or CD44 expression, or high CD8 tumour-infiltrating lymphocyte (TIL) counts suggesting that therapy could be tapered for many if patients could be identified individually. Patients treated curatively, with HPV DNA/p16 positive tumours examined for HLA class I and II, CD44 and CD8 TILs, were included. An L1-regularised logistic regression was used to evaluate the effect of the biomarker data, age, stage, diagnosis, smoking and treatment on 3-year risk of death or relapse on a training cohort of 197 patients diagnosed 2000–2007 and validated on a cohort of 118 patients diagnosed 2008–2011. The variables finally included in the model were HLA class I, CD8 TILs, age, stage and diagnosis (TSCC or BOTSCC). The model showed acceptable discrimination and calibration. The discriminative ability of the model did not diminish after validation (AUC = 0.77). To our knowledge, this is the first model to utilise information from several markers to predict an individual probability of clinical outcome for patients with HPV DNA/p16 positive tumours.
    Keywords: Hpv ; Tonsillar Cancer ; Base of Tongue Cancer ; Biomarkers ; Survival ; Medicine
    ISSN: 0959-8049
    E-ISSN: 1879-0852
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  • 3
    Language: English
    In: Anticancer research, February 2017, Vol.37(2), pp.665-673
    Description: Human papillomavirus (HPV) is a favourable prognostic factor in oropharyngeal cancer. Moreover, we and others reported that HPV-positive cancer of unknown primary in the head and neck region (HNCUP) has better outcome than HPV-negative HNCUP. However, not all studies concord. Here, our previous finding was investigated in a new cohort and additional biomarkers were analyzed. A total of 19 HNCUPs diagnosed 2008-2013 were analyzed for HPV DNA by polymerase chain reaction assay (PCR) and p16 by immunohistochemistry (IHC). Thereafter, 69 HNCUPs diagnosed between 2000-2013 were analyzed for HPV16 mRNA by PCR (if HPV16DNA-positive) and cluster of differentiation 8 positive (CD8) tumour-infiltrating lymphocytes (TILs) and human leukocyte antigen (HLA) class I-expression using IHC. HPV DNA, alone and in combination with p16 overexpression, was validated as a favourable prognostic factor in HNCUP. HPV16 mRNA was present in most HPV16 DNA-positive cases, confirming HPV-driven carcinogenesis in HNCUP. High CD8 TIL counts indicated favourable prognosis. HPV status is useful for the management of patients with HNCUP and the role of CD8 TILs should be further explored.
    Keywords: Human Papillomavirus ; Head and Neck Cancer ; Lymphocytes ; Neoplasms ; Oropharyngeal Cancer ; Tumor-Infiltrating ; Unknown Primary ; Biomarkers, Tumor -- Immunology ; Cd8-Positive T-Lymphocytes -- Immunology ; Head and Neck Neoplasms -- Immunology ; Lymphocytes, Tumor-Infiltrating -- Immunology ; Neoplasms, Unknown Primary -- Immunology ; Papillomavirus Infections -- Immunology
    ISSN: 09297049
    E-ISSN: 1791-7530
    E-ISSN: 17444136
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  • 4
    Language: English
    In: Cancer Medicine, 2013, Vol. 2(4), pp. 507-18
    Description: Patients with human papillomavirus DNA positive (HPVDNA+) oropharyngeal squamous cell carcinoma (OSCC) have better clinical outcome than those with HPV DNA negative (HPVDNA-) OSCC upon intensive oncological treatment. All HPVDNA+ OSCC patients may not require intensive treatment, however, but before potentially deintensifying treatment, additional predictive markers are needed. Here, we examined HPV, p16(INK4a), and CD44 in OSCC in correlation to clinical outcome. Pretreatment tumors from 290 OSCC patients, the majority not receiving chemotherapy, were analyzed for HPV DNA by Luminex and for p16(INK4a) and CD44 by immunohistochemistry. 225/290 (78%) tumors were HPVDNA+ and 211/290 (73%) overexpressed p16(INK4a), which correlated to presence of HPV (P 〈 0.0001). Presence of HPV DNA, absent/weak CD44 intensity staining correlated to favorable 3-year disease-free survival (DFS) and overall survival (OS) by univariate and multivariate analysis, and likewise for p16(INK4a) by univariate analysis. Upon stratification for HPV, HPVDNA+ OSCC with absent/weak CD44 intensity presented the significantly best 3-year DFS and OS, with 〉95% 3-year DFS and OS. Furthermore, in HPVDNA+ OSCC, p16(INK4a)+ overexpression correlated to a favorable 3-year OS. In conclusion, patients with HPVDNA+ and absent/weak CD44 intensity OSCC presented the best survival and this marker combination could possibly be used for selecting patients for tailored deintensified treatment in prospective clinical trials. Absence of/weak CD44 or presence of human papillomavirus (HPV) DNA was shown as a favorable prognostic factors in tonsillar and tongue base cancer. Moreover, patients with the combination of absence of/weak CD44 and presence of HPV DNA presented a very favorable outcome. Therefore, we suggest that this marker combination could potentially be used to single out patients with a high survival that could benefit from a de-escalated oncological treatment.
    Keywords: Hpv ; Cd44 ; Human Papillomavirus ; Oropharyngeal Cancer ; Prognosis ; Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi ; Onkologi ; Oncology
    ISSN: 2045-7634
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  • 5
    Language: English
    In: Oral Oncology, May 2014, Vol.50(5), pp.491-497
    Description: Presence of HPV DNA was analyzed in mouthwash and tonsillar swab samples, if indicative of HPV-positive tonsillar or base of tongue cancer in 76 patients, with suspected head neck cancer, undergoing diagnostic endoscopy at Karolinska University Hospital. The diagnosis and tumor HPV status was later obtained from patients’ records. As controls, 37 tumor-free dental visitors were included. Of the 76 patients, 22/29 (76%) and 16/18 (89%) had an HPV-positive tonsillar and base of tongue cancer respectively, with 18/22 (82%) and 8/16 (50%) respectively having tumor concordant HPV-type positive oral samples. Two other HPV-positive oral samples in the base of tongue cancer group did not correlate to the tumor HPV status. Among the remaining patients, 19 with other head neck cancer and 10 with benign conditions, 4/29 (14%) had HPV-positive oral samples. Consequently, of the HPV-positive oral samples, dominated by HPV16 and high signals, 27/32 (84%) were derived from 26 patients with concordant HPV-type positive tonsillar or base of tongue cancer and one patient with an unknown primary head and neck cancer. The other five HPV-positive oral samples, with mainly low signals were derived from two patients with non-concordant HPV-type positive tumor biopsies, two patients with HPV-negative tumor biopsies and a patient with a benign condition. Of the dental patients, 3/37 (8%) had HPV-positive tonsillar swabs with weak signals. In patients with suspected head neck cancer, HPV-positive oral samples, especially HPV16 with high signals, could be indicative of HPV-positive tonsillar or base of tongue cancer.
    Keywords: Human Papillomavirus (Hpv) ; Oral Hpv Infection ; Mouthwash Samples, Tonsillar Swabs ; Oropharyngeal Squamous Cell Carcinoma ; Tonsillar Cancer Base of Tongue Cancer ; Medicine ; Dentistry
    ISSN: 1368-8375
    E-ISSN: 1879-0593
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  • 6
    Language: English
    In: Oral Oncology, September 2015, Vol.51(9), pp.857-861
    Description: Hypopharyngeal cancer is a subset of head neck squamous cell carcinoma (HNSCC) with particularly poor prognosis. Human papillomavirus (HPV) is a risk factor for some HNSCC, and its presence is of prognostic value for certain subsites. However, its influence on survival in hypopharyngeal cancer has not been thoroughly investigated. Here we examine HPV DNA and p16 (p16) overexpression in relation to clinical outcome. Hypopharyngeal tumour biopsies from 82 patients diagnosed 2008–2013 were examined for presence of HPV DNA by a bead-based multiplex assay and for p16 expression by immunohistochemistry, and the obtained data compared to that acquired previously from 109 patients diagnosed 2000–2007 at the same clinic. A survival analysis was then performed on 142 patients (from both studies) treated with curative intent and a 3-year follow-up time. Of the tumour biopsies 3/82 (3.7%) were HPV16 DNA and p16 positive, while 12/82 (14.6%) were p16 positive, equivalent to that in the previous study. Overall 3-year survival was significantly more favourable for patients with HPV16 DNA and p16 positive tumours as compared to survival of the other patients (86% vs. 31%, = 0.0185). A similar but not statistically significant trend was found for disease specific survival. HPV DNA and p16 positive hypopharyngeal cancer was rare and had not increased, but had a better clinical outcome as compared to other HPV-unrelated hypopharyngeal cancer. In addition, p16 overexpression was not a suitable surrogate marker for presence of HPV or for prediction of survival in this type of cancer.
    Keywords: Hpv ; P16 ; Hypopharyngeal Cancer ; Overall Survival ; Disease Specific Survival ; Medicine ; Dentistry
    ISSN: 1368-8375
    E-ISSN: 1879-0593
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  • 7
    In: Head & Neck, March 2017, Vol.39(3), pp.419-426
    Description: Byline: , , Linnea Haeggblom, Nikolaos Tertipis, Nathalie Grun, Cinzia Bersani, Linda Marklund, Mehran Ghaderi, Anders Nasman, Torbjorn Ramqvist, Torbjorn Ramqvist, Torbjorn Ramqvist, Torbjorn Ramqvist, Tina Dalianis Abstract Background Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has a better outcome than most head neck squamous cell carcinomas (HNSCCs) and an HPV-positive lymph node metastasis likely has an HPV-positive oropharyngeal SCC origin. Determining HPV-status in cervical lymph nodes by fine-needle aspiration cytology (FNAC) may be useful for diagnosis. Methods FNACs from 66 patients with neck masses were prospectively examined for HPV DNA and HPV16 mRNA by a polymerase chain reaction (PCR)-based assay, and the data correlated to diagnosis and HPV-status obtained from histopathological specimens. Results Aspirates from 17 of 66 patients, later diagnosed with HPV-positive oropharyngeal SCC, were HPV16 DNA-positive. HPV16 mRNA was detected in all cases with extractable RNA. All remaining FNACs, including 18 branchial cleft cysts, were HPV DNA-negative. HPV DNA status in the aspirates showed perfect concordance with corresponding biopsies. Conclusion HPV16 DNA detection in fine-needle aspirations from neck masses is reliable and HPV16 DNA in a metastasis is a strong indicator of an HPV-positive oropharyngeal SCC. [c] 2016 Wiley Periodicals, Inc. Head Neck 39: 419-426, 2017 Article Note: Lars Sivars, David Landin, Cecilia Nordfors, Eva Munck-Wikland, Edneia Tani, and Tina Dalianis contributed equally to this work.
    Keywords: Human Papillomavirus ; Head And Neck Cancer ; Oropharyngeal Cancer ; Fine‐Needle Aspiration ; Fine‐Needle Biopsy
    ISSN: 1043-3074
    E-ISSN: 1097-0347
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  • 8
    Language: English
    In: Oral Oncology, May 2017, Vol.68, pp.53-59
    Description: Head-neck cancer therapy has become intensified. With radiotherapy alone, 3-year disease-free survival (DFS) is 80% for HPV-positive TSCC/BOTSCC and better for patients with favorable characteristics, suggesting therapy could be tapered for some, decreasing side-effects. Therefore, we built a model to predict progression-free survival for patients with HPV-positive TSCC and BOTSCC. TSCC/BOTSCC patients treated curatively between 2000 and 2011, with HPV16 DNA/E7 mRNA positive tumors examined for CD8 TILs, HPV16 mRNA and HLA class I expression were included. Patients were split randomly 65/35 into training and validation sets, and LASSO regression was used to select a model in the training set, the performance of which was evaluated in the validation set. 258 patients with HPV DNA/E7 mRNA positive tumors could be included, 168 and 90 patients in the respective sets. No treatment improved prognosis compared to radiotherapy alone. CD8 TIL counts and young age were the strongest predictors of survival, followed by T-stage 〈3 and presence of HPV16 E2 mRNA. The model had an area under curve (AUC) of 76%. A model where the presence of three of four of these markers defined good prognosis captured 56% of non-relapsing patients with a positive predictive value of 98% in the validation set. Furthermore, the model identified 35% of our cohort that was overtreated and could safely have received de-escalated therapy. CD8 TIL counts, age, T-stage and E2 expression could predict progression-free survival, identifying patients eligible for randomized trials with milder treatment, potentially reducing side effects without worsening prognosis.
    Keywords: Hpv ; Oropharyngeal Cancer Tonsillar Cancer ; Base of Tongue Cancer ; Biomarkers ; Survival ; Medicine ; Dentistry
    ISSN: 1368-8375
    E-ISSN: 1879-0593
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